{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T16:32:30Z","timestamp":1773160350030,"version":"3.50.1"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:00:00Z","timestamp":1506384000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:00:00Z","timestamp":1506384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Influenza is an annual seasonal epidemic that has continually drawn public attentions, due to the potential death toll and drug resistance. Neuraminidase, which is essential for the spread of influenza virus, has been regarded as a valid target for the treatment of influenza infection. Although neuraminidase drugs have been developed, they are susceptible to drug-resistant mutations in the sialic-binding site. In this study, we established computational models (site-moiety maps) of H1N1 and H5N1 to determine properties of the 150-cavity, which is adjacent to the drug-binding site. The models reveal that hydrogen-bonding interactions with residues R118, D151, and R156 and van der Waals interactions with residues Q136, D151, and T439 are important for identifying 150-cavitiy inhibitors. Based on the models, we discovered three new inhibitors with IC<jats:sub>50<\/jats:sub> values &lt;10\u2009\u03bcM that occupies both the 150-cavity and sialic sites. The experimental results identified inhibitors with similar activities against both wild-type and dual H274Y\/I222R mutant neuraminidases and showed little cytotoxic effects. Furthermore, we identified three new inhibitors situated at the sialic-binding site with inhibitory effects for normal neuraminidase, but lowered effects for mutant strains. The results suggest that the new inhibitors can be used as a starting point to combat drug-resistant strains.<\/jats:p>","DOI":"10.1038\/s41598-017-12101-3","type":"journal-article","created":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T14:05:37Z","timestamp":1505916337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of neuraminidase inhibitors against dual H274Y\/I222R mutant strains"],"prefix":"10.1038","volume":"7","author":[{"given":"Kai-Cheng","family":"Hsu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Chen","family":"Hung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Chun","family":"HuangFu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Ying","family":"Sung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony","family":"Eight Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Yu","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I-Jung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikhil","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John T.-A.","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinn-Moon","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,26]]},"reference":[{"key":"12101_CR1","doi-asserted-by":"publisher","first-page":"2872","DOI":"10.2174\/092986707782360024","volume":"14","author":"Y Liu","year":"2007","unstructured":"Liu, Y., Zhang, J. & Xu, W. Recent progress in rational drug design of neuraminidase inhibitors. Curr. Med. Chem. \n                           14, 2872\u20132891 (2007).","journal-title":"Curr. Med. Chem."},{"key":"12101_CR2","first-page":"130","volume":"29","author":"SC Chang","year":"2006","unstructured":"Chang, S. C., Cheng, Y. Y. & Shih, S. R. Avian influenza virus: the threat of a pandemic. Chang Gung Med. J. \n                           29, 130\u2013134 (2006).","journal-title":"Chang Gung Med. J."},{"key":"12101_CR3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015314","volume":"5","author":"Z Zhang","year":"2010","unstructured":"Zhang, Z. et al. Spatio-temporal data comparisons for global highly pathogenic avian influenza (HPAI) H5N1 outbreaks. PLoS One \n                           5, e15314 (2010).","journal-title":"PLoS One"},{"key":"12101_CR4","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1503\/cmaj.090866","volume":"181","author":"T Tanaka","year":"2009","unstructured":"Tanaka, T. et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. Can. Med. Assoc. J. \n                           181, 55\u201358 (2009).","journal-title":"Can. Med. Assoc. J."},{"key":"12101_CR5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/nature05114","volume":"443","author":"RJ Russell","year":"2006","unstructured":"Russell, R. J. et al. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature \n                           443, 45\u201349 (2006).","journal-title":"Nature"},{"key":"12101_CR6","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/0042-6822(74)90458-9","volume":"59","author":"P Palese","year":"1974","unstructured":"Palese, P., Schulman, J. L., Bodo, G. & Meindl, P. Inhibition of influenza and parainfluenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA). Virology \n                           59, 490\u2013498 (1974).","journal-title":"Virology"},{"key":"12101_CR7","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1021\/jm001070j","volume":"44","author":"T Wang","year":"2001","unstructured":"Wang, T. & Wade, R. C. Comparative binding energy (COMBINE) analysis of influenza neuraminidase-inhibitor complexes. J. Med. Chem. \n                           44, 961\u2013971 (2001).","journal-title":"J. Med. Chem."},{"key":"12101_CR8","first-page":"583","volume":"64","author":"GD Appiah","year":"2015","unstructured":"Appiah, G. D. et al. Influenza Activity - United States, 2014-15 Season and Composition of the 2015-16 Influenza Vaccine. Mmwr-Morbid Mortal W. \n                           64, 583\u2013590 (2015).","journal-title":"Mmwr-Morbid Mortal W."},{"key":"12101_CR9","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S2213-2600(14)70041-4","volume":"2","author":"SG Muthuri","year":"2014","unstructured":"Muthuri, S. G. et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Resp. Med. \n                           2, 395\u2013404 (2014).","journal-title":"Lancet Resp. Med."},{"key":"12101_CR10","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nature05003","volume":"443","author":"M Luo","year":"2006","unstructured":"Luo, M. Structural biology: antiviral drugs fit for a purpose. Nature \n                           443, 37\u201338 (2006).","journal-title":"Nature"},{"key":"12101_CR11","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1517\/14656566.2015.1066336","volume":"16","author":"MM McLaughlin","year":"2015","unstructured":"McLaughlin, M. M., Skoglund, E. W. & Ison, M. G. Peramivir: an intravenous neuraminidase inhibitor. Expert Opin. Pharmacother. \n                           16, 1889\u20131900 (2015).","journal-title":"Expert Opin. Pharmacother."},{"key":"12101_CR12","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1128\/AAC.00333-08","volume":"53","author":"M Yamashita","year":"2009","unstructured":"Yamashita, M. et al. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity. Antimicrob. Agents Chemother. \n                           53, 186\u2013192 (2009).","journal-title":"Antimicrob. Agents Chemother."},{"key":"12101_CR13","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/S0162-3109(99)00184-8","volume":"47","author":"RA Burger","year":"2000","unstructured":"Burger, R. A. et al. Immunological effects of the orally administered neuraminidase inhibitor oseltamivir in influenza virus-infected and uninfected mice. Immunopharmacology \n                           47, 45\u201352 (2000).","journal-title":"Immunopharmacology"},{"key":"12101_CR14","doi-asserted-by":"publisher","first-page":"423","DOI":"10.2174\/156802606776743138","volume":"6","author":"K Klumpp","year":"2006","unstructured":"Klumpp, K. & Graves, B. J. Optimization of small molecule drugs binding to highly polar target sites: lessons from the discovery and development of neuraminidase inhibitors. Curr. Top. Med. Chem. \n                           6, 423\u2013434 (2006).","journal-title":"Curr. Top. Med. Chem."},{"key":"12101_CR15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002249","volume":"7","author":"CJ Vavricka","year":"2011","unstructured":"Vavricka, C. J. et al. Structural and functional analysis of laninamivir and its octanoate prodrug reveals group specific mechanisms for influenza NA inhibition. PLoS Pathog. \n                           7, e1002249 (2011).","journal-title":"PLoS Pathog."},{"key":"12101_CR16","doi-asserted-by":"publisher","first-page":"2633","DOI":"10.1056\/NEJMp058291","volume":"353","author":"A Moscona","year":"2005","unstructured":"Moscona, A. Oseltamivir resistance\u2013disabling our influenza defenses. New Engl. J. Med. \n                           353, 2633\u20132636 (2005).","journal-title":"New Engl. J. Med."},{"key":"12101_CR17","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1056\/NEJMc1003749","volume":"363","author":"E van der Vries","year":"2010","unstructured":"van der Vries, E., Stelma, F. F. & Boucher, C. A. B. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. New Engl. J. Med. \n                           363, 1381\u20131382 (2010).","journal-title":"New Engl. J. Med."},{"key":"12101_CR18","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1056\/NEJMoa054512","volume":"353","author":"MD de Jong","year":"2005","unstructured":"de Jong, M. D. et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. New Engl. J. Med. \n                           353, 2667\u20132672 (2005).","journal-title":"New Engl. J. Med."},{"key":"12101_CR19","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1086\/656439","volume":"51","author":"HT Nguyen","year":"2010","unstructured":"Nguyen, H. T., Fry, A. M., Loveless, P. A., Klimov, A. I. & Gubareva, L. V. Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y\/I223R mutation from a child after prolonged treatment with oseltamivir. Clin. Infect. Dis. \n                           51, 983\u2013984 (2010).","journal-title":"Clin. Infect. Dis."},{"key":"12101_CR20","doi-asserted-by":"publisher","first-page":"6539","DOI":"10.1039\/C6OB00999A","volume":"14","author":"C Colombo","year":"2016","unstructured":"Colombo, C., Pinto, B. M., Bernardi, A. & Bennet, A. J. Synthesis and evaluation of influenza A viral neuraminidase candidate inhibitors based on a bicyclo[3.1.0]hexane scaffold. Org. Biomol. Chem. \n                           14, 6539\u20136553 (2016).","journal-title":"Org. Biomol. Chem."},{"key":"12101_CR21","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.antiviral.2014.12.004","volume":"114","author":"JL McKimm-Breschkin","year":"2015","unstructured":"McKimm-Breschkin, J. L. & Barrett, S. Neuraminidase mutations conferring resistance to laninamivir lead to faster drug binding and dissociation. Antiviral Res. \n                           114, 62\u201366 (2015).","journal-title":"Antiviral Res."},{"key":"12101_CR22","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.g2545","volume":"348","author":"T Jefferson","year":"2014","unstructured":"Jefferson, T. et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. Bmj-Brit. Med. J. \n                           348, g2545 (2014).","journal-title":"Bmj-Brit. Med. J."},{"key":"12101_CR23","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j2841","volume":"357","author":"Z Kmietowicz","year":"2017","unstructured":"Kmietowicz, Z. WHO downgrades oseltamivir on drugs list after reviewing evidence. BMJ \n                           357, j2841 (2017).","journal-title":"BMJ"},{"key":"12101_CR24","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1111\/j.1750-2659.2011.00304.x","volume":"6","author":"GM Air","year":"2012","unstructured":"Air, G. M. Influenza neuraminidase. Influenza Other Respi. Viruses \n                           6, 245\u2013256 (2012).","journal-title":"Influenza Other Respi. Viruses"},{"key":"12101_CR25","doi-asserted-by":"publisher","first-page":"10493","DOI":"10.1128\/JVI.00959-08","volume":"82","author":"X Xu","year":"2008","unstructured":"Xu, X., Zhu, X., Dwek, R. A., Stevens, J. & Wilson, I. A. Structural characterization of the 1918 influenza virus H1N1 neuraminidase. J. Virol. \n                           82, 10493\u201310501 (2008).","journal-title":"J. Virol."},{"key":"12101_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1114","volume":"1","author":"S Rudrawar","year":"2010","unstructured":"Rudrawar, S. et al. Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase. Nat. Commun. \n                           1, 113 (2010).","journal-title":"Nat. Commun."},{"key":"12101_CR27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/bip.22130","volume":"99","author":"L Tolentino-Lopez","year":"2013","unstructured":"Tolentino-Lopez, L. et al. Outside-binding site mutations modify the active site\u2019s shapes in neuraminidase from influenza A H1N1. Biopolymers \n                           99, 10\u201321 (2013).","journal-title":"Biopolymers"},{"key":"12101_CR28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037095","volume":"7","author":"J LeGoff","year":"2012","unstructured":"LeGoff, J. et al. I223R mutation in influenza A(H1N1)pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y. PLoS One \n                           7, e37095 (2012).","journal-title":"PLoS One"},{"key":"12101_CR29","doi-asserted-by":"publisher","first-page":"4364","DOI":"10.1021\/bi300561n","volume":"51","author":"CJ Woods","year":"2012","unstructured":"Woods, C. J. et al. Long time scale GPU dynamics reveal the mechanism of drug resistance of the dual mutant I223R\/H275Y neuraminidase from H1N1-2009 influenza virus. Biochemistry \n                           51, 4364\u20134375 (2012).","journal-title":"Biochemistry"},{"key":"12101_CR30","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1021\/jm8001197","volume":"51","author":"LS Cheng","year":"2008","unstructured":"Cheng, L. S. et al. Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase. J. Med. Chem. \n                           51, 3878\u20133894 (2008).","journal-title":"J. Med. Chem."},{"key":"12101_CR31","volume":"8","author":"A Hoffmann","year":"2017","unstructured":"Hoffmann, A. et al. Discovery and characterization of diazenylaryl sulfonic acids as inhibitors of viral and bacterial neuraminidases. Front. Microbiol. \n                           8, 205 (2017).","journal-title":"Front. Microbiol."},{"key":"12101_CR32","first-page":"W424","volume-title":"Nucleic Acids Res.","author":"YF Chen","year":"2010","unstructured":"Chen, Y. F. et al. SiMMap: a web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties. Nucleic Acids Res. 38, (W424\u2013W430 (2010)."},{"issue":"Suppl 1","key":"12101_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-S1-S33","volume":"12","author":"KC Hsu","year":"2011","unstructured":"Hsu, K. C., Chen, Y. F., Lin, S. R. & Yang, J. M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics \n                           12(Suppl 1), S33 (2011).","journal-title":"BMC Bioinformatics"},{"key":"12101_CR34","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-014-2525-9","volume":"21","author":"LRS Gema","year":"2015","unstructured":"Gema, L. R. S. et al. Targeting a cluster of arginine residues of neuraminidase to avoid oseltamivir resistance in influenza A (H1N1): a theoretical study. J. Mol. Model. \n                           21, 8 (2015).","journal-title":"J. Mol. Model."},{"key":"12101_CR35","doi-asserted-by":"publisher","first-page":"11808","DOI":"10.1073\/pnas.94.22.11808","volume":"94","author":"JN Varghese","year":"1997","unstructured":"Varghese, J. N. et al. Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases. Proc. Natl. Acad. Sci. USA \n                           94, 11808\u201311812 (1997).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"12101_CR36","doi-asserted-by":"publisher","first-page":"4433","DOI":"10.1128\/AAC.00334-09","volume":"53","author":"AC Hurt","year":"2009","unstructured":"Hurt, A. C., Holien, J. K. & Barr, I. G. In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses. Antimicrob. Agents Chemother. \n                           53, 4433\u20134440 (2009).","journal-title":"Antimicrob. Agents Chemother."},{"key":"12101_CR37","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1002\/pro.5560040606","volume":"4","author":"JN Varghese","year":"1995","unstructured":"Varghese, J. N., Epa, V. C. & Colman, P. M. Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase. Protein Sci. \n                           4, 1081\u20131087 (1995).","journal-title":"Protein Sci."},{"key":"12101_CR38","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1046\/j.1432-1327.1998.2580320.x","volume":"258","author":"AA Ghate","year":"1998","unstructured":"Ghate, A. A. & Air, G. M. Site-directed mutagenesis of catalytic residues of influenza virus neuraminidase as an aid to drug design. Eur. J. Biochem. \n                           258, 320\u2013331 (1998).","journal-title":"Eur. J. Biochem."},{"key":"12101_CR39","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1038\/nature06956","volume":"453","author":"PJ Collins","year":"2008","unstructured":"Collins, P. J. et al. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature \n                           453, 1258\u20131261 (2008).","journal-title":"Nature"},{"key":"12101_CR40","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1021\/jm800455g","volume":"52","author":"J An","year":"2009","unstructured":"An, J. et al. A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase. J. Med. Chem. \n                           52, 2667\u20132672 (2009).","journal-title":"J. Med. Chem."},{"key":"12101_CR41","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s00726-008-0201-z","volume":"37","author":"M Malaisree","year":"2009","unstructured":"Malaisree, M. et al. Source of oseltamivir resistance in avian influenza H5N1 virus with the H274Y mutation. Amino Acids \n                           37, 725\u2013732 (2009).","journal-title":"Amino Acids"},{"key":"12101_CR42","doi-asserted-by":"publisher","first-page":"7188","DOI":"10.1128\/AAC.03667-14","volume":"58","author":"A Eshaghi","year":"2014","unstructured":"Eshaghi, A. et al. Multiple influenza A (H3N2) mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient. Antimicrob. Agents Chemother. \n                           58, 7188\u20137197 (2014).","journal-title":"Antimicrob. Agents Chemother."},{"key":"12101_CR43","doi-asserted-by":"publisher","first-page":"11892","DOI":"10.1021\/ja073992i","volume":"129","author":"JJ Shie","year":"2007","unstructured":"Shie, J. J. et al. Synthesis of tamiflu and its phosphonate congeners possessing potent anti-influenza activity. J. Am. Chem. Soc. \n                           129, 11892\u201311893 (2007).","journal-title":"J. Am. Chem. Soc."},{"key":"12101_CR44","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1021\/jm980162u","volume":"41","author":"CU Kim","year":"1998","unstructured":"Kim, C. U. et al. Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors. J. Med. Chem. \n                           41, 2451\u20132460 (1998).","journal-title":"J. Med. Chem."},{"key":"12101_CR45","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.antiviral.2008.10.006","volume":"81","author":"HC Hung","year":"2009","unstructured":"Hung, H. C. et al. Aurintricarboxylic acid inhibits influenza virus neuraminidase. Antiviral Res. \n                           81, 123\u2013131 (2009).","journal-title":"Antiviral Res."},{"key":"12101_CR46","doi-asserted-by":"publisher","first-page":"3321","DOI":"10.1016\/S0960-894X(98)00587-3","volume":"8","author":"W Lew","year":"1998","unstructured":"Lew, W. et al. A new series of C3-aza carbocyclic influenza neuraminidase inhibitors: synthesis and inhibitory activity. Biorg. Med. Chem. Lett. \n                           8, 3321\u20133324 (1998).","journal-title":"Biorg. Med. Chem. Lett."},{"key":"12101_CR47","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1016\/S0960-894X(97)00333-8","volume":"7","author":"MA Williams","year":"1997","unstructured":"Williams, M. A. et al. Structure-activity relationships of carbocyclic influenza neuraminidase inhibitors. Biorg. Med. Chem. Lett. \n                           7, 1837\u20131842 (1997).","journal-title":"Biorg. Med. Chem. Lett."},{"key":"12101_CR48","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1016\/S0968-0896(99)00197-2","volume":"7","author":"VR Atigadda","year":"1999","unstructured":"Atigadda, V. R. et al. Hydrophobic benzoic acids as inhibitors of influenza neuraminidase. Biorg. Med. Chem. \n                           7, 2487\u20132497 (1999).","journal-title":"Biorg. Med. Chem."},{"key":"12101_CR49","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1086\/318537","volume":"183","author":"LV Gubareva","year":"2001","unstructured":"Gubareva, L. V., Kaiser, L., Matrosovich, M. N., Soo-Hoo, Y. & Hayden, F. G. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J. Infect. Dis. \n                           183, 523\u2013531 (2001).","journal-title":"J. Infect. Dis."},{"key":"12101_CR50","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","volume":"22","author":"K Arnold","year":"2006","unstructured":"Arnold, K., Bordoli, L., Kopp, J. & Schwede, T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics \n                           22, 195\u2013201 (2006).","journal-title":"Bioinformatics"},{"key":"12101_CR51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056704","volume":"8","author":"KC Hsu","year":"2013","unstructured":"Hsu, K. C. et al. Parallel screening of wild-type and drug-resistant targets for anti-resistance neuraminidase inhibitors. PLoS One \n                           8, e56704 (2013).","journal-title":"PLoS One"},{"key":"12101_CR52","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1021\/acs.jcim.5b00331","volume":"56","author":"M Yusuf","year":"2016","unstructured":"Yusuf, M. et al. H274Y\u2019s effect on oseltamivir resistance: What happens before the drug enters the binding site. J. Chem. Inf. Model. \n                           56, 82\u2013100 (2016).","journal-title":"J. Chem. Inf. Model."},{"key":"12101_CR53","doi-asserted-by":"publisher","first-page":"8787","DOI":"10.1128\/JVI.00477-06","volume":"80","author":"HL Yen","year":"2006","unstructured":"Yen, H. L. et al. Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses. J. Virol. \n                           80, 8787\u20138795 (2006).","journal-title":"J. Virol."},{"key":"12101_CR54","first-page":"208","volume":"21","author":"G Nicola","year":"2012","unstructured":"Nicola, G., Liu, T. Q., Hwang, L. & Gilson, M. BindingDB: A protein-ligand database for drug discovery. Protein Sci. \n                           21, 208\u2013208 (2012).","journal-title":"Protein Sci."},{"key":"12101_CR55","unstructured":"Berthold, M. R. et al. In Studies in Classification, Data Analysis, and KNowledge Organization (GfKL 2\n                           007) (Springer, 2007)."},{"key":"12101_CR56","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1128\/JVI.02485-14","volume":"89","author":"YH Baek","year":"2015","unstructured":"Baek, Y. H. et al. Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. J. Virol. \n                           89, 287\u2013299 (2015).","journal-title":"J. Virol."},{"key":"12101_CR57","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/nrm2183","volume":"8","author":"RH Adams","year":"2007","unstructured":"Adams, R. H. & Alitalo, K. Molecular regulation of angiogenesis and lymphangiogenesis. Nature Reviews Molecular Cell Biology \n                           8, 464\u2013478 (2007).","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"12101_CR58","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1177\/135965350601100804","volume":"11","author":"Y Abed","year":"2006","unstructured":"Abed, Y., Baz, M. & Boivin, G. Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds. Antivir. Ther. \n                           11, 971\u2013976 (2006).","journal-title":"Antivir. Ther."},{"key":"12101_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6029","volume":"5","author":"S Duan","year":"2014","unstructured":"Duan, S. et al. Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses. Nat. Commun. \n                           5, 5029 (2014).","journal-title":"Nat. Commun."},{"key":"12101_CR60","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.jmgm.2009.07.001","volume":"28","author":"Y Li","year":"2009","unstructured":"Li, Y., Zhou, B. C. & Wang, R. X. Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1. J. Mol. Graph. Model. \n                           28, 203\u2013219 (2009).","journal-title":"J. Mol. Graph. Model."},{"key":"12101_CR61","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1093\/protein\/11.9.739","volume":"11","author":"IN Shindyalov","year":"1998","unstructured":"Shindyalov, I. N. & Bourne, P. E. Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. Protein Eng. \n                           11, 739\u2013747 (1998).","journal-title":"Protein Eng."},{"key":"12101_CR62","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1021\/ci00020a039","volume":"34","author":"J Sadowski","year":"1994","unstructured":"Sadowski, J., Gasteiger, J. & Klebe, G. Comparison of automatic three-dimensional model builders using 639 x-ray structures. J. Chem. Inf. Comput. Sci. \n                           34, 1000\u20131008 (1994).","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"12101_CR63","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1021\/acs.jcim.6b00465","volume":"57","author":"SJ Capuzzi","year":"2017","unstructured":"Capuzzi, S. J., Muratov, E. N. & Tropsha, A. Phantom PAINS: Problems with the Utility of Alerts for Pan-Assay INterference CompoundS. J. Chem. Inf. Model. \n                           57, 417\u2013427 (2017).","journal-title":"J. Chem. Inf. Model."},{"key":"12101_CR64","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1016\/j.drudis.2016.02.004","volume":"21","author":"MR Senger","year":"2016","unstructured":"Senger, M. R., Fraga, C. A., Dantas, R. F. & Silva, F. P. Jr. Filtering promiscuous compounds in early drug discovery: is it a good idea? Drug Discov. Today \n                           21, 868\u2013872 (2016).","journal-title":"Drug Discov. Today"},{"key":"12101_CR65","unstructured":"Dassault Syst\u00e8mes BIOVIA (2017). BIOVIA Discovery Studio 2017 R2: A comprehensive predictive science application for the Life Sciences. San Diego, CA, USA http:\/\/accelrys.com\/products\/collaborative-science\/biovia-discovery-studio\/."},{"key":"12101_CR66","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1002\/jcc.21287","volume":"30","author":"BR Brooks","year":"2009","unstructured":"Brooks, B. R. et al. CHARMM: the biomolecular simulation program. J. Comput. Chem. \n                           30, 1545\u20131614 (2009).","journal-title":"J. Comput. Chem."},{"key":"12101_CR67","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S0076-6879(09)63014-7","volume":"463","author":"DL Jarvis","year":"2009","unstructured":"Jarvis, D. L. Baculovirus-Insect Cell Expression Systems. Guide to Protein Purification, Second Edition \n                           463, 191\u2013222 (2009).","journal-title":"Guide to Protein Purification, Second Edition"},{"key":"12101_CR68","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/0003-2697(79)90362-2","volume":"94","author":"M Potier","year":"1979","unstructured":"Potier, M., Mameli, L., Belisle, M., Dallaire, L. & Melancon, S. B. Fluorometric assay of neuraminidase with a sodium (4-methylumbelliferyl-alpha-D-N-acetylneuraminate) substrate. Anal. Biochem. \n                           94, 287\u2013296 (1979).","journal-title":"Anal. Biochem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12101-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12101-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12101-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:24:50Z","timestamp":1671794690000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12101-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,26]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["12101"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-12101-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,26]]},"assertion":[{"value":"13 June 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12336"}}